Protein tyrosine kinases are currently recognized as important molecular targets for drug development in the treatment of several disorders, particularly in the treatment of proliferative disorders. Dysregulation of tyrosine kinase activity has emerged as a major mechanism by which cancer cells evade normal physiological constraints on growth, proliferation and survival. One of the key focus areas in anti-TK drug discovery is the design and development of small molecules that can directly inhibit catalytic activity of the kinase by interfering with the binding of ATP or substrates. An important advantage of TK-directed therapy is the possibility to perform pharmacodynamic studies that correlate inhibition of the targeted TK in cancer cells with clinical responses to the drug.
Classical tyrosine kinase inhibitors, which are predominantly the Bcr-Abl kinase inhibitors that are currently in clinical use, are described in the following patent literature:                U.S. Pat. No. 5,521,184 (the '184 patent): Exemplifies 4-[(Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-phenyl]benzamide methanesulfonate (Imatinib mesylate, Gleevec®)        U.S. Pat. No. 7,169,791 (the '791 patent): Exemplifies 4-Methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide (Nilotinib, Tasigna®)        U.S. Pat. No. 6,596,746 (the '746 patent): Exemplifies N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (Dasatinib, Sprycel®)        
While the second generation TK inhibitors in clinic viz. nilotinib and dasatinib have provided additional treatment option to patients who have developed resistance to imatinib, there are certain shortcomings with regard to their side effects. Particularly in the case of dasatinib, the increased potency may be associated with untoward off-target toxicities, which probably relate to their inhibitory activity against a broader range of protein kinases such as Kit, PDGFR and ephrin receptor (EphA2) tyrosine kinases which are directly implicated in haematopoiesis, control of tissue interstitial-fluid pressure and angiogenesis. These effects may provide the physiological explanation for some of the toxicities associated with dasatinib therapy such as myelosuppression and pleural effusion. Besides, treatment with highly potent Abl kinase inhibition has potential for the development of cardiotoxicity in patients with CML.
Studies have shown that patients taking imatinib develop resistance to the drug during the course of therapy. Recent research has provided a better understanding of the mechanism of resistance which led to the development of second generation TK inhibitors. Although the second generation TK inhibitors in clinic provide treatment alternatives for patients who develop resistance to imatinib therapy, the prognosis for the patients having T315I mutation is not good since none of these currently marketed therapies are effective. There is thus an unmet medical need with regard to treatment of patients having the T315I mutation. Omacetaxine (homoharringtonine) is approved by the FDA for CML patients with T315I. However, it is an intravenous drug with a non-specific mechanism of action. Ariad Compound Ponatinib (AP24534, U.S. Pat. No. 8,114,874) is also approved by US FDA but has a boxed warning for risk-threatening blood clots and severe narrowing of blood vessels. Other drug candidates in clinical phase include the Deciphera compound DCC-2036 (PCT Publication No. WO 2008/046003). The present applicant previously reported novel diarylacetylene hydrazides as tyrosine kinase inhibitors published as WO 2012/098416 A1.
The current invention describes novel amidoheteroaryl aroyl hydrazide ethynes containing compounds which are not only potent inhibitors of Abl tyrosine kinase but also on its mutant versions.